Cadmium is an environmental and occupational hazard and is capable of causing renal damage upon chronic exposure. This element, which has no known biological function, accumulates with increasing duration of exposure. A majority of cadmium is retained in liver and kidney where it induces and binds to metallothionein - a low molecular weight sulfhydryl- rich protein. Intracellular metallothionein appears to function as a detoxifying protein. However, with continued exposure, the intracellular cadmium-metallothionein complex is released into the circulation. In addition, cadmium absorbed from the intestine may also be released in this form. Because cadmium-metallothionein has a low molecular weight, it is filtered in the renal glomeruli. A majority of the metalloprotein is reabsorbed by the renal proximal tubular epithelial cells and the remaining is excreted in urine. The exogenous cadmium-metallothionein is highly nephrotoxic and is believed to be responsible for the chronic nephrotoxicity of cadmium. This proposal describes studies that will investigate the biochemical mechanism of renal toxicity of cadmium by using the: a) subchronic cadmium chloride injection rat model, b) acute cadmium-metallothionein injection rat model, and c) the acute cadmium chloride injection hamster model. Specifically, the intracellular renal metallothionein and the relative amounts of cadmium associated with this and other ligands during various stages of cadmium exposure will be determined. Additionally, various biochemical parameters will be examined as possible targets of cadmium toxicity.